On July 12, 2015 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that in the IMvigor 210 study, the investigational cancer immunotherapy atezolizumab (MPDL3280A; anti-PDL1) shrank tumors (objective response rate; ORR; the primary end point of this Phase II study) in people with locally advanced or metastatic urothelial bladder cancer (UBC) who had progressed on initial treatment (second-line or later) (Press release, Genentech, JUL 12, 2015, View Source [SID:1234506533]). High amounts of PD-L1 (Programmed Death Ligand-1) expression by a person’s cancer correlated with increased response to the medicine. Adverse events were consistent with what has been previously observed for atezolizumab.

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"We are encouraged by the number of people who responded to atezolizumab and maintained their response during the study because minimal progress has been made in advanced bladder cancer for nearly 30 years," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "We plan to present results at an upcoming medical meeting, and will discuss next steps with health authorities to bring a new treatment option to patients as soon as possible."

Last year, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for atezolizumab in people whose metastatic bladder cancer expresses PD-L1. This designation is designed to expedite the development and review of medicines intended to treat serious diseases.

About IMvigor 210

IMvigor 210 is an open-label, multicenter, single-arm Phase II study that evaluated the safety and efficacy of atezolizumab in people with locally advanced or metastatic UBC, regardless of PD-L1 expression. People in the study were enrolled into one of two cohorts. Cohort 1 consisted of people who had received no prior therapies for locally advanced or metastatic UBC, but who were ineligible for first-line cisplatin-based therapy; results for this cohort are not yet mature. Cohort 2, for which results were announced today, included people whose disease progressed during or following previous treatment with a platinum-based chemotherapy regimen (second-line or later). People received a 1200-milligram intravenous dose of atezolizumab on day one of 21-day cycles until progressive disease (Cohort 1) or loss of clinical benefit (Cohort 2). The primary endpoint of the study was ORR. Secondary endpoints included duration of response (DoR), overall survival (OS), progression-free survival (PFS) and safety. PD-L1 expression was assessed using an investigational immunohistochemistry (IHC) test being developed by Roche Diagnostics.

In addition to the IMvigor 210, Genentech has an ongoing randomized Phase III study, IMvigor 211, comparing atezolizumab with standard-of-care chemotherapy in people who have relapsed UBC, and a planned Phase III study, IMvigor 010, that will evaluate atezolizumab compared with observation in people with early-stage muscle-invasive bladder cancer who are selected for PD-L1 expression and are at risk for recurrence (adjuvant). All studies include the evaluation of a companion test developed by Roche Diagnostic to determine PD-L1 status.

About metastatic urothelial bladder cancer

Metastatic urothelial bladder cancer is associated with a poor prognosis and limited treatment options. According to the American Cancer Society (ACS), it is estimated that more than 74,000 Americans will be diagnosed with bladder cancer in 2015, and approximately 15,000 of new diagnoses are made when bladder cancer is in advanced stages. There is a dramatic difference in survival rates between early and advanced bladder cancer. The ACS estimates that approximately 15 percent of people with advanced bladder cancer (stage IV) will live for five years, compared to 88 percent when diagnosed during stage I. Men are about three to four times more likely to get bladder cancer during their lifetime than women.

About atezolizumab

Atezolizumab (also known as MPDL3280A; anti-PDL1) is an investigational monoclonal antibody designed to interfere with a protein called PD-L1. Atezolizumab is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, atezolizumab may enable the activation of T cells.

All studies of atezolizumab include the evaluation of an investigational IHC test that uses the antibody SP142 to measure PD-L1 expression on both tumor cells and infiltrating immune cells. The goal of PD-L1 as a biomarker is to identify those people most likely to benefit when treated with atezolizumab alone, and to determine which people may benefit most from a combination of atezolizumab and another medicine. There are 11 ongoing or planned Phase III studies of atezolizumab across certain kinds of lung, kidney, breast and bladder cancer.

On July 12, 2015 Provectus Pharmaceuticals reported studies presented at the European Society for Medical Oncology 17th World Congress on Gastrointestinal cancer, Barcelona, Spain,1-4 July, helped define the hepatocellular carcinoma and liver metastatic colorectal cancer patient populations in which established treatments work best and provided insights into emerging therapies (Press release, Provectus Pharmaceuticals, JUL 12, 2015, View Source [SID:1234506324]).Patients with hepatocellular carcinoma (HCC) have a poor prognosis with median survivals of 10 to 11 months despite use of sorafenib first line. Liver metastases develop in nearly 20% of patients with stage II and 50% of patients with stage III colorectal cancer and represent the major cause death in this disease. Unfortunately, radical surgical resection of liver metastases is only possible in 10 to 25% of patients with CRC confined to the liver. In most patients the number, localization and/or size of the liver metastases or poor hepatic reserve preclude resection. All this points to the unmet medical need for both HCC and metastatic liver cancer.

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The latest analysis of the GIDEON study, which set out to evaluate the safety of sorafenib in a real world population of HCC patients, showed improved outcomes for patients over 70 years compared to those under 70 years. The current subgroup analysis explored 278 patients from the Italian cohort of the main study, of whom 141 were older than 70 years and 133 younger.

Results showed that the median overall survival was 10 months in the younger age group versus 20 months in the older age group. Furthermore, elderly patients had a PFS of 6 months versus 4.1 months for younger patients; and elderly patients had a time to progression of 7.6 months versus 5 months for younger patients. The authors believe that younger patients have shorter overall survivals due to more advanced disease.

The latest sub-analysis from the SIRFLOX study showed patients with metastatic colorectal cancer (mCRC) that has spread only to the liver at study entry do better with selective internal radiation therapy (SIRT) than those with more widespread metastases.

With SIRT, a technique granted CE Mark approval in the EU in 2002 for unresectable liver tumours, yttrium-9-resin microspheres (Sirtex) are delivered to the liver via a hepatic artery injection. Key to the success of the procedure is occlusion of extra-hepatic vessels to prevent deposition of radioactive microspheres outside the liver. Since there have never been large randomized controlled trials for SIRT in combination with modern first-line standard of care chemotherapy the SIRFLOX study was initiated.

Data presented at ASCO (Free ASCO Whitepaper) 2015 failed to show overall progression free survival advantages for patients treated with mFOLFOX6 + SIRT compared to those treated with chemotherapy alone. The findings were attributed to the inclusion of 40% of patients with extra-hepatic metastatic disease in the analysis.

In the current sub-group analysis the investigators explored the 318 patients with metastases limited to the liver at the time they entered the study separately from the 212 patients with both liver and extra hepatic metastases at study entry.

Results showed that for those treated with metastases limited to the liver median PFS in the liver was 21.1 months for those treated with chemotherapy + SIRT compared to 12.4 months for those treated with chemotherapy alone (p=0.003, HR 0.64). "These new pre-planned sub-group findings for PFS in the liver should lead oncologists to consider adding SIR-Spheres Y-90 resin microspheres to first-line chemotherapy," said Guy van Hazel, the co-principal investigator of the SIRFLOX study, from the University of Western Australia, Perth.

Rose bengal solution as hepatocellular carcinoma treatment
According to one intriguing abstract study, a single injection with PV-10 led to the complete disappearance of HCC in one patient, and colorectal liver metastases in another. PV-10, a 10% solution of rose bengal used originally to stain necrotic tissue in the cornea, has been showing promise in melanoma. A phase 2 study, presented at ESMO (Free ESMO Whitepaper) last year, demonstrated that 50% of patients with stage III melanoma patients who had all their cutaneous lesions injected with PV-10 achieved a complete response.

For the current study two cohorts of patients, one with non-resectable HCC (n=6) and a second with other forms of cancer metastatic to the liver (n=7, three originally colorectal tumors, two nonsmall cell lung, two melanoma and one ovarian) underwent a single percutaneous injection of PV-10 guided by CT to one target lesion in the liver at least 1 cm in diameter.

From the analysis of the first five patients (who had six tumours injected) the investigators found that two patients showed no evidence of disease at more than 40 months follow-up according to RECIST and EASL criteria. The first patient was a 68 year old male with HCC (hepatitis B and cirrhosis) alive at 54 months follow-up with no evidence of disease; while the second patient was a 61-year-old male with metastatic CRC alive at 42 months follow-up with no evidence of disease.

"Having liver cancer patients alive at up to 54 months follow-up with no evidence of disease is remarkable. This is even more extraordinary when you consider these patients received just one or two intralesional injections," says Eric Wachter, the author of the abstract who co-developed PV-10.

As with melanoma, the mechanism of PV-10 in liver cancers is believed to be due to local chemoablative effects where the agents enters lysosomes causing tumor necrosis that can stimulate immunological effects.

Furthermore, melanoma patients injected with PV-10 have been shown to have increased T cells in peripheral blood, including CD8+, CD4+, CD3+ and NKT.

On July 12, 2015 Varian Medical Systems reported the Koo Foundation Sun Yat-Sen Cancer Center (KF-SYSCC) has established an entirely paperless and filmless clinical process in radiation oncology, designed to enhance patient safety as well as operational efficiency (Press release, InfiMed, JUL 12, 2015, View Source [SID:1234506321]). Using the ARIA oncology information system from Varian Medical Systems (NYSE: VAR), the clinical team has automated essential tasks, built in safety-checks, and centralized patient information for easier access by staff members.

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ARIA combines a comprehensive, oncology-specific patient electronic medical record (EMR) with numerous tools for managing clinical, administrative and financial operations in multidisciplinary cancer care settings.

"We were using both Varian and Siemens information management software, but we standardized on Varian’s ARIA platform. Within three months we had removed all paper charts from the department," said Yeh-Chi Lo, Ph.D., chief of the Department of Medical Physics. "Varian and its local agent, Cooperative C.L. Enterprise Co., provided us with valuable assistance, helping us to configure the ARIA software to manage different types of treatment, and to reflect our preferences in terms of clinical work flow. The software is set up to interrupt the clinical workflow at critical junctures unless specific safety checks have been completed and documented."

"Conversion to an electronic process actually made our workflow more efficient, and potentially safer due to careful automation of essential steps," added Skye Hung-Chun Cheng M.D., chief of the Department of Radiation Oncology. "Our goal was to become a fully paperless and filmless department. ARIA has also enhanced the communication between our clinical team members."

The KF-SYSCC Radiation Therapy Department is a mixed-vendor environment, treating patients on three Varian linear accelerators including a TrueBeam system plus a Primus-M machine from Siemens.

Seven radiation oncologists working with nine medical physicists at the cancer center offer patients a broad range of advanced treatments, including intensity-modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT), RapidArc radiotherapy, stereotactic radiosurgery (SRS), and stereotactic body radiotherapy (SBRT). Clinicians use respiratory gating to compensate for breathing motion during treatments for lung or breast cancer.

The cancer center also manages high-dose-rate brachytherapy and seed implant procedures using the ARIA platform, resulting in one comprehensive database of patient information that can be mined for insights about trends and outcomes.

"The future of health care will center on the use of evidence-based protocols within a pay-for-performance framework," said Dr. Cheng. "Realizing that vision will rely on our ability to mine our clinical data–something that would not be feasible without a comprehensive EMR like ARIA."

"The Radiation Therapy Department of the Koo Foundation Sun Yat-Sen Cancer Center is the first department in Taiwan to use ARIA to establish a fully paperless clinical environment," said Zhang Xiao, Varian’s vice president and managing director of the greater China region. "Varian commends the clinical and management teams for being forward-looking thought leaders in the use of digital technology to improve the quality of cancer care."

On July 9, 2015 Epizyme reported that it has amended and restated its agreement with Celgene Corporation to extend the research collaboration between the two companies for at least three additional years (Filing, 8-K, Epizyme, JUL 9, 2015, View Source [SID:1234506203]). Under the collaboration, Celgene will have the option to license histone methyltransferase (HMT) inhibitors being developed by Epizyme against three predefined targets.

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Under the terms of the revised agreement:
• Epizyme will receive a $10 million extension fee from Celgene in return for an option to individually license global rights for two of the targets and ex-US rights for the third target.
• Celgene may exercise its option with respect to each of the targets at the time of the IND filing for an additional pre-specified license payment.
• Epizyme will be responsible for leading and funding development for each target candidate through phase 1 clinical trials.
• Following the completion of phase 1, if Celgene chooses to continue its license for a specific target, it may do so by making an additional pre-specified payment.
• Epizyme may earn total potential milestones of up to $610 million on the three targets, including up to $75 million in development milestones and license fees, $365 million in regulatory milestones, and $170 million in sales milestones
• Epizyme also may earn a royalty of up to a low double-digit percentage on worldwide net sales for two of the product candidates, and on ex-US net sales for the third product candidate.
• Epizyme will retain global rights to the remainder of its pipeline, as Celgene’s option to license ex-US rights for any other preclinical programs will terminate.

In addition, Celgene will retain its ex-US license to, and the companies will continue their ongoing clinical collaboration on, pinometostat (EPZ-5676), a HMT inhibitor targeting DOT1L. Pinometostat is in phase 1 development for the treatment of patients with acute leukemia with alterations in the MLL gene (MLL-r).

"We believe that the extension of our agreement with Celgene will accelerate our goal of developing new therapies that have the potential to help many patients with epigenetically driven cancers," said Robert Gould, Ph.D., President and Chief Executive Officer, Epizyme. "Celgene is a leading company in oncology development and commercialization and we are pleased to continue our partnership on pinometostat and these three exciting novel targets."

The term of this agreement is based on specific development milestones, including the timing of IND filings and completion of phase 1 studies, but will extend for a minimum of three years. In addition, Celgene will no longer have the right of first negotiation on a business combination with Epizyme.

Financial Update
The Company also announced today that, based on its current operating plans, it projects that its cash and cash equivalents will be sufficient to fund operations through at least the end of the second quarter of 2017, prior to including any potential option exercise fees or future milestone payments. This new cash outlook reflects a significant reallocation of resources, implementation of cost savings initiatives, the additional capital provided from the Celgene extension fee payment and the partial exercise of the overallotment option in April from the Company’s March public financing.

"We have increased investment in tazemetostat development, both as a single agent and in future studies in combination with other agents," said Andrew Singer, Executive Vice President and Chief Financial Officer at Epizyme. "This required reprioritizing our pipeline development plans and reducing operating costs. We are excited about the updated data from our dose escalation and dose expansion studies presented at the International Congress on Malignant Lymphoma in Lugano, Switzerland on June 20. We look forward to presenting additional data at the European Society for Medical Oncology’s European Cancer Congress in Vienna, Austria on September 26."

About Tazemetostat (EPZ-6438)

Epizyme is developing tazemetostat for the treatment of non-Hodgkin lymphoma patients and patients with INI1-deficient solid tumors. Tazemetostat is a first-in-class small molecule inhibitor of EZH2 developed by Epizyme. In many human cancers, aberrant EZH2 enzyme activity results in misregulation of genes that control cell proliferation resulting in the rapid and unconstrained growth of tumor cells. Tazemetostat is the WHO International Non-Proprietary Name (INN) for compound EPZ-6438.

Tazemetostat is the second HMT inhibitor to enter human clinical development (following Epizyme’s DOT1L inhibitor, pinometostat).

Epizyme is conducting a five-arm, multi-center international phase 2 clinical trial that will assess the safety and activity of tazemetostat in patients with relapsed or refractory non-Hodgkin lymphoma. A phase 1 dose escalation and dose expansion trial of tazemetostat is also ongoing, with additional data expected to be reported later in 2015. Additional information about this program, including clinical trial information, may be found here: View Source

About Pinometostat (EPZ-5676)

Epizyme is developing pinometostat, a small molecule inhibitor of DOT1L created with Epizyme’s proprietary product platform, for the treatment of patients with acute leukemia in which the MLL gene is rearranged due to a chromosomal translocation (MLL-r). Due to these rearrangements, DOT1L is misregulated, resulting in the increased expression of genes causing leukemia. Pinometostat is the WHO International Non-Proprietary Name (INN) for compound EPZ-5676.

Epizyme believes that pinometostat was the first HMT inhibitor to enter human clinical development. Epizyme is currently conducting a two-stage Phase 1 study in adult MLL-r patients
and in May 2014, initiated a Phase 1b study of pinometostat in pediatric patients with rearrangements of the MLL gene. The adult dose escalation cohorts have completed enrollment, and an adult MLL-r dose expansion cohort is now enrolling patients. Additional information about these ongoing Phase 1 studies can be found here: View Source

Pinometostat has been granted orphan drug designation for the treatment of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) by the Food and Drug Administration in the U.S. and by the European Commission in Europe.

Epizyme retains all U.S. rights to pinometostat and has granted Celgene an exclusive license to pinometostat outside of the U.S.

On July 9, 2015 Eli Lilly reported the U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) met today to discuss the data supporting Eli Lilly and Company’s necitumumab in combination with gemcitabine and cisplatin for use in first-line treatment of patients with advanced squamous non-small cell lung cancer (NSCLC) (Press release, Eli Lilly, JUL 9, 2015, View Source [SID:1234506198]).

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Squamous NSCLC is a devastating and difficult-to-treat form of lung cancer. The five-year survival rate for patients with metastatic disease is less than five percent.[1] Necitumumab in combination with gemcitabine and cisplatin is the first regimen to show a significant improvement in overall survival over chemotherapy alone, specifically in the first-line setting.

"We are encouraged by the Committee’s constructive discussion on the benefit-risk profile of necitumumab as few advances have been made over the past two decades in the first-line treatment of advanced squamous NSCLC, leaving a significant unmet medical need," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "We believe necitumumab with gemcitabine and cisplatin represents a meaningful advance in the search for a new first-line treatment option and look forward to working closely with the FDA as they continue their review."

The FDA is expected to make a decision on Lilly’s biologics license application for necitumumab later this year.

About Necitumumab
Necitumumab is a recombinant human IgG1 monoclonal antibody that is designed to block the ligand binding site of the human epidermal growth factor receptor 1 (EGFR). Activation of EGFR has been correlated with malignant progression, induction of angiogenesis and inhibition of apoptosis or cell death.

About Squamous Non-Small Cell Lung Cancer (NSCLC)
NSCLC is the most common type of lung cancer, and accounts for about 85 percent of all lung cancer cases.[2] Squamous NSCLC, which represents about 30 percent of all people affected by NSCLC,[3] is a devastating, difficult-to-treat form of the disease. Patients face an imposing disease and symptom burden with very poor prognosis; the five-year survival rate for patients with metastatic disease is less than five percent.[4] Little progress has been made over the last two decades, particularly in the first-line setting, leaving a significant unmet medical need. In order to address the unique and complex needs of individual patients with advanced squamous NSCLC, more first-line treatment options are needed.